Abstract
Augmented renal clearance (ARC) as observed in the critically ill (pediatric) population can have a major impact on the pharmacokinetics and posology of renally excreted drugs. Although sepsis has been described as a major trigger in the development of ARC in human critically ill patients, mechanistic insights on ARC are currently lacking. An appropriate ARC animal model could contribute to reveal these underlying mechanisms. In this exploratory study, a state of ARC was induced in 8-week-old piglets. Conscious piglets were continuously infused over 36 h with lipopolysaccharides (LPS) from Escherichia coli (O111:B4) to induce sepsis and subsequently trigger ARC. To study the dose-dependent effect of LPS on the renal function, three different doses (0.75, 2.0, 5.0 μg/kg/h) were administered (two ♂ piglets/dose, one sham piglet), in combination with fluid administration (0.9% NaCl) at 6 ml/kg/h. Single boluses of renal markers, i.e., creatinine [40 mg/kg body weight (BW)], iohexol (64.7 mg/kg BW), and para-aminohippuric acid (PAH, 10 mg/kg BW) were administered intravenously to evaluate the effect of LPS on the renal function. Clinical parameters were monitored periodically. Blood sampling was performed to determine the effect on hematology, neutrophil gelatinase-associated lipocalin, and prostaglandin E2 plasma levels. All piglets that were continuously infused with LPS displayed an elevated body temperature, heart rhythm, and respiratory rate ~1–3 h after start of the infusion. After infusion, considerably higher total body clearances of iohexol, creatinine, and PAH were observed, independent of the administration of LPS and/or its dose. Since also the sham piglet, receiving no LPS, demonstrated a comparable increase in renal function, the contribution of fluid administration to the development of ARC should be further evaluated.
Highlights
Sepsis and septic shock are both significant causes of morbidity and mortality in the intensive care population
After the start of the LPS administration, an increase in body temperature (BT) was observed in all LPS-challenged piglets
The complex nature of human sepsis have contributed to the development of experimental sepsis animal models to study the human pathophysiology of sepsis [24]
Summary
Sepsis and septic shock are both significant causes of morbidity and mortality in the intensive care population. The phenomenon of augmented renal clearance (ARC) has increasingly been recognized in subsets of critically ill (pediatric) patients, with sepsis being suggested as one of the main triggers [4, 7,8,9,10,11] These patients display a considerably enhanced drug excretion, potentially leading to subtherapeutic concentrations. Increased dosages may be necessary to maintain therapeutic concentrations of various renally excreted drugs This is relevant for renally excreted antibiotics in critically ill patients, since detrimental effects of altered drug disposition on morbidity and mortality have been suggested [9]. An appropriate ARC animal model that could be obtained through the induction of sepsis would contribute to reveal these underlying mechanisms
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